This competing renewal application builds on substantial progress that was made in the initial cycle of this grant in the development of gene transfer to heart and liver for treating heart disease and atherosclerosis. The structure of the grant has not changed in the renewal with includes projects by Drs. Wilson, Sweeney and Rader as well as Vector, Cell Morphology and Administrative Cores. The goals of the current cycle of this P01 have been realized resulting in 63 publications. The renewal application builds on this progress. The overall goal of the renewal grant is the development of effective gene therapy for cardiovascular disease, which can be achieved by targeting the heart and liver. An important theme in the renewal is that one needs to understand the biology and pathogenesis of the vectors systems used and the target diseases in order to realize this goal. In Project 1, Dr. Wilson will exploit their recent discovery of a new family of AAVs broadly distributed throughout non-human primate populations to create better vectors for targeting heart and liver and to learn more about the biology of natural AAV infections in the context of the use of AAV vectors. Dr. Sweeney, in Project 2, will develop methods to target cardiac myocytes with vectors to further define the mechanisms underlying the progressive development of dilated cardiomyopathy and failure following myocardial infarction and the hypertrophy that develops in the setting of chronic pressure overload. In Project 3, Dr. Rader will utilize techniques of liver directed gene transfer to study and potentially treat two diseases of apoB-containing lipoproteins: familial hypercholesterolemia and abetalipoproteinemia. Vectors developed in Project 1 will be evaluated in terms of the needs of Projects 2 and 3. The Vector Core will produce and characterize materials used in all projects while the Cell Morphology Core will provide support in the in vivo analysis of gene transfer and characterization of vector preparations.